No

Angiotensin-Converting Enzyme (ACE) Inhibitors

Management of mild to severe hypertension; treatment of congestive heart failure, left ventricular dysfunction after myocardial infarction

Investigational: Severe congestive heart failure in infants, neonatal hypertension, acute pulmonary edema

C/D (2nd and 3rd trimesters)

Clinical effects on the fetus: No data available on crossing the placenta. Cranial defects, hypocalvaria/acalvaria, oligohydramnios, persistent anuria following delivery, hypotension, renal defects, renal dysgenesis/dysplasia, renal failure, pulmonary hypoplasia, limb contractures secondary to oligohydramnios and stillbirth reported. ACE inhibitors should be avoided during pregnancy.

Breast-feeding/lactation: Crosses into breast milk. Detectable levels but appears clinically insignificant. American Academy of Pediatrics considers compatible with breast-feeding.

Hypersensitivity to enalapril or enalaprilat; angioedema related to previous treatment with an ACE inhibitor; patients with idiopathic or hereditary angioedema; bilateral renal artery stenosis; primary hyperaldosteronism; pregnancy (2nd and 3rd trimesters)

Anaphylactic reactions can occur. Angioedema can occur at any time during treatment (especially following first dose). Careful blood pressure monitoring with first dose (hypotension can occur especially in volume depleted patients). Dosage adjustment needed in renal impairment. Use with caution in hypovolemia; collagen vascular diseases; valvular stenosis (particularly aortic stenosis); hyperkalemia; or before, during, or immediately after anesthesia. Avoid rapid dosage escalation which may lead to renal insufficiency. Hypersensitivity reactions may be seen during hemodialysis with high-flux dialysis membranes (eg, AN69). Hyperkalemia may rarely occur. Neutropenia/agranulocytosis with myeloid hyperplasia can rarely occur. If patient has renal impairment then a baseline WBC with differential and serum creatinine should be evaluated and monitored closely during the first 3 months of therapy. Use with caution in unilateral renal artery stenosis and pre-existing renal insufficiency.

Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with congestive heart failure. However, the frequency of adverse effects associated with placebo is also increased in this population.

Cardiovascular: Hypotension (0.9% to 6.7%), chest pain (2%), syncope (0.5% to 2%), orthostasis (2%), orthostatic hypotension (2%)

Central nervous system: Headache (2% to 5%), dizziness (4% to 8%), fatigue (2% to 3%), weakness (2%)

Dermatologic: Rash (1.5%) Gastrointestinal: Abnormal taste, abdominal pain, vomiting, nausea, diarrhea, anorexia, constipation

Neuromuscular & skeletal: Weakness

Renal: Increased serum creatinine (0.2% to 20%), worsening of renal function (in patients with bilateral renal artery stenosis or hypovolemia)

Respiratory (1% to 2%): Bronchitis, cough, dyspnea

<1% (Limited to important or life-threatening symptoms): Angina pectoris, pulmonary edema, palpitations, arrest, CVA, myocardial infarction, rhythm, insomnia, ataxia, drowsiness, confusion, depression, nervousness, vertigo, alopecia, erythema multiforme, pruritus, Stevens-Johnson syndrome, urticaria, angioedema, pemphigus, hypoglycemia, hyperkalemia, gynecomastia, stomatitis, xerostomia, dyspepsia, glossitis, pancreatitis, ileus, urinary tract infection. impotence, agranulocytosis, neutropenia, anemia, hemolysis with G-6-PD, jaundice, hepatitis, paresthesia, blurred vision, conjunctivitis, tinnitus, oliguria, renal dysfunction, asthma, bronchospasm, URI, diaphoresis. Worsening of renal function may occur in patients with bilateral renal artery stenosis or in hypovolemic patients.

Case reports: Schönlein-Henoch purpura, toxic pustuloderma, toxic epidermal necrolysis, exfoliative dermatitis, pemphigus foliaceous, photosensitivity, sicca syndrome, systemic lupus erythematosus, giant cell arteritis, depression, hallucinations, psychosis, lichen-form reaction, ototoxicity. A syndrome which may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia and positive ANA, and elevated ESR has been reported for enalapril and other ACE inhibitors.

Mild hypotension has been the only toxic effect seen with acute overdose. Bradycardia may also occur; hyperkalemia occurs even with therapeutic doses, especially in patients with renal insufficiency and those taking NSAIDs

Following initiation of essential overdose management, toxic symptom treatment and supportive treatment should be initiated. Hypotension usually responds to I.V. fluids or Trendelenburg positioning.

CYP3A3/4 enzyme substrate

Aspirin and NSAIDs may decrease ACE inhibitor efficacy and/or increase risk of renal adverse effects.

Diuretics: Hypovolemia due to diuretics may precipitate acute hypotensive events or acute renal failure.

Insulin: Risk of hypoglycemia may be increased.

Lithium: Risk of lithium toxicity may be increased; monitor lithium levels, especially in the first 4 weeks of therapy.

Mercaptopurine: Risk of neutropenia may be increased.

Potassium-sparing diuretics (amiloride, spironolactone, triamterene): Increased risk of hyperkalemia.

Potassium supplements may increase the risk of hyperkalemia.

Trimethoprim (high dose) may increase the risk of hyperkalemia.

Enalaprilat: Clear, colorless solution which should be stored at <30°C; I.V. is 24 hours at room temperature in D₅W or NS

Competitive inhibitor of angiotensin-converting enzyme (ACE); prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor; results in lower levels of angiotensin II which causes an increase in plasma renin activity and a reduction in aldosterone secretion

Oral:

Onset of action: ~1 hour

Duration: 12-24 hours

Absorption: Oral: 55% to 75%

Protein binding: 50% to 60%

Metabolism: Enalapril is a prodrug and undergoes biotransformation to enalaprilat in the liver

Half-life:

Enalapril: Adults:

Healthy: 2 hours

With congestive heart failure: 3.4-5.8 hours

Enalaprilat:

Infants 6 weeks to 8 months: 6-10 hours

Adults: 35-38 hours

Time to peak serum concentration: Oral:

Enalapril: Within 0.5-1.5 hours

Enalaprilat (active): Within 3-4.5 hours

Elimination: Principally in urine (60% to 80%) with some fecal excretion

Use lower listed initial dose in patients with hyponatremia, hypovolemia, severe congestive heart failure, decreased renal function, or in those receiving diuretics.

Investigational initial oral doses of enalapril: 0.1 mg/kg/day increasing as needed over 2 weeks to 0.5 mg/kg/day have been used to treat severe congestive heart failure in infants.

Investigational I.V. doses of enalaprilat: 5-10 mcg/kg/dose administered every 8-24 hours have been used for the treatment of neonatal hypertension. Monitor patients carefully; select patients may require higher doses.

Adults:

Oral: Enalapril

Hypertension: 2.5-5 mg/day then increase as required, usual therapeutic dose for hypertension: 10-40 mg/day in 1-2 divided doses. Note: Initiate with 2.5 mg if patient is taking a diuretic which cannot be discontinued. May add a diuretic if blood pressure cannot be controlled with enalapril alone.

Heart failure: As adjunct with diuretics and digitalis, initiate with 2.5 mg once or twice daily (usual range: 5-20 mg/day in 2 divided doses; maximum: 40 mg)

Asymptomatic left ventricular dysfunction: 2.5 mg twice daily, titrated as tolerated to 20 mg/day

I.V.: Enalaprilat

Hypertension: 1.25 mg/dose, given over 5 minutes every 6 hours; doses as high as 5 mg/dose every 6 hours have been tolerated for up to 36 hours. Note: If patients are concomitantly receiving diuretic therapy, begin with 0.625 mg I.V. over 5 minutes; if the effect is not adequate after 1 hour, repeat the dose and administer 1.25 mg at 6-hour intervals thereafter; if adequate, administer 0.625 mg I.V. every 6 hours.

Heart failure: Avoid I.V. administration in patients with unstable heart failure or those suffering acute myocardial infarction.

Conversion from I.V. to oral therapy if not concurrently on diuretics: 5 mg once daily; subsequent titration as needed; if concurrently receiving diuretics and responding to 0.625 mg I.V. every 6 hours, initiate with 2.5 mg/day.

Dosing adjustment in renal impairment:

Oral: Enalapril:

Cl_cr 30-80 mL/minute: Administer 5 mg/day titrated upwards to maximum of 40 mg.

Cl_cr <30 mL/minute: Administer 2.5 mg day; titrated upward until blood pressure is controlled.

For heart failure patients with sodium <130 mEq/L or serum creatinine >1.6 mg/dL, initiate dosage with 2.5 mg/day, increasing to twice daily as needed. Increase further in increments of 2.5 mg/dose at >4-day intervals to a maximum daily dose of 40 mg.

I.V.: Enalaprilat:

Cl_cr >30 mL/minute: Initiate with 1.25 mg every 6 hours and increase dose based on response.

Cl_cr <30 mL/minute: Initiate with 0.625 mg every 6 hours and increase dose based on response.

Hemodialysis: Moderately dialyzable (20% to 50%); administer dose postdialysis (eg, 0.625 mg I.V. every 6 hours) or administer 20% to 25% supplemental dose following dialysis; Clearance: 62 mL/minute.

Peritoneal dialysis: Supplemental dose is not necessary, although some removal of drug occurs.

Dosing adjustment in hepatic impairment: Hydrolysis of enalapril to enalaprilat may be delayed and/or impaired in patients with severe hepatic impairment, but the pharmacodynamic effects of the drug do not appear to be significantly altered; no dosage adjustment.

Limit salt substitutes or potassium-rich diet; avoid natural licorice (causes sodium and water retention and increases potassium loss)

Blood pressure, renal function, WBC, serum potassium; blood pressure monitor required during intravenous administration

Positive Coombs' [direct]; may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent

Enalapril should be prescribed twice daily for congestive heart failure. Enalaprilat should be used with caution and avoided if possible in the acute treatment of myocardial infarction. In a study to evaluate enalaprilat therapy administered within the first 24 hours of the onset of acute myocardial infarction therapy worsened survival.

ACE-inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. When ACE inhibition is introduced in patients with pre-existing diuretic therapy who are hypovolemic, the ACE inhibitor may induce acute hypotension. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, angiotensin-receptor blocker therapy instituted. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.

May cause drowsiness and dizziness; rarely may cause insomnia, confusion, depression

May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; may decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels

No information available to require special precautions

No effects or complications reported

Take exactly as directed; do not discontinue without consulting prescriber. Take first dose at bedtime. Take all doses on an empty stomach (30 minutes before or 2 hours after meals). This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. Do not use potassium supplements or salt substitutes containing potassium without consulting prescriber. May cause dizziness, fainting, lightheadedness (use caution when driving or engaging in tasks that require alertness until response to drug is known); postural hypotension (use caution when rising from lying or sitting position or climbing stairs); nausea, vomiting, abdominal pain, dry mouth, or transient loss of appetite (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help) - report if these persist. Report chest pain or palpitations; mouth sores; fever or chills; swelling of extremities, face, mouth, or tongue; skin rash; numbness, tingling, or pain in muscles; difficulty in breathing or unusual cough; or other persistent adverse reactions. Pregnancy precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures.

May cause depression in some patients; discontinue if angioedema of the face, extremities, lips, tongue, or glottis occurs; watch for hypotensive effects within 1-3 hours of first dose or new higher dose

Injection, as enalaprilat: 1.25 mg/mL (1 mL, 2 mL)

Tablet, as maleate: 2.5 mg, 5 mg, 10 mg, 20 mg

An enalapril oral suspension (0.2 mg/mL) has been made using one 2.5 mg tablet and 12.5 mL sterile water; stability unknown; suspension should be used immediately and the remaining amount discarded

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